Rigor before speculation in COVID-19 therapy

to the editor: In a recent letter, “Covid-19 infection and mortality: a physiologist’s perspective enlightening clinical features and plausible interventional strategies,” Abassi et al. (1) misinterpret the literature and reach conclusions that are contrary to the facts and out of alignment with current consensus.

The causative virus of COVID-19, SARS-CoV-2, enters host nasal epithelial cells, bronchial epithelial cells, and type II alveolar cells by binding to angiotensin-converting enzyme 2 (ACE2), which is a key enzymatic component of the counterregulatory pathway of the renin-angiotensin-aldosterone system (RAAS). The interface of ACE2 and SARS-CoV-2 has fueled tremendous speculation about a link between popularly prescribed drug classes that inhibit the RAAS and COVID-19 severity.

Abassi et al. state that “preliminary available data from infected patients illustrate that patients treated with angiotensin-II inhibitors (ACE-I)/angiotensin receptor blockers (ARBs) or nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit severe symptoms with a higher mortality rate as compared with nonuser counterparts.” In fact, the three articles that are cited as evidence, including a study of 1,099 patients published in the New England Journal of Medicine, never mention if the patients were treated with angiotensin-converting enzyme inhibitors (ACEis)/ARBs/NSAIDs (2). Our ongoing review of the literature (see http://www.nephjc.com/news/covidace2) indicates that there is currently no clinical data to support the notion that ACEi or ARB use increases the risk of more-severe COVID-19. We await ongoing randomized clinical trials and properly designed observational studies addressing this issue.

Concern that ACEi or ARB exposure could possibly increase risk comes from several studies in animal models demonstrating increased ACE2 expression, and Abassi et al. cite several of those studies. However, they do not acknowledge the other animal and human studies that found no increase in ACE2 expression or activity during treatment with an ACEi or ARB (6, 11). To the best of our knowledge, no animal or human studies have been reported that examined the effect of ACEi or ARB exposure on ACE2 expression in the lung. Moreover, a change in ACE2 of modest magnitude does not necessarily imply more or less infectivity.

Abassi et al. do not discuss the other side of ACE2 in COVID-19. Loss of ACE2 activity has been proposed to drive disease severity. ACE2 is a carboxypeptidase that cleaves angiotensin II (Ang II) to generate Ang-(1–7), thereby dampening the effects of Ang II. Ang-(1–7) acts on the Mas receptor to induce actions that oppose the Ang II signaling pathway, including reducing inflammation and fibrosis and increasing nitric oxide production (9). Because SARS-CoV targets ACE2 for endocytosis and degradation (3, 5), it has been speculated that viral infection might shift the balance of RAAS signaling toward increased Ang II and decreased Ang-(1–7) in the lung, leading to an increase in proinflammatory cytokine release (12), and the hyperinflammatory state of COVID-19. The idea follows, in part, from studies in a mouse model of acid inhalation-induced lung injury enhanced by SARS-CoV spike protein (derived from the 2003 SARS epidemic) that showed decreased ACE2 expression. Moreover, lung injury in the model was attenuated by the ARB losartan (5, 11). Obviously, studies are required to determine if these observations can be extrapolated to COVID-19 in humans.

In the rush to find a cure for COVID-19, the frenzied effort created an unfortunate wake of unsubstantiated editorials and premature or poorly designed and hastily executed studies. Remarkably, the reach is vast, from preprint servers to highly reputable scientific journals. Abassi et al. are not alone in putting speculation ahead of scientific rigor. Based on an incomplete review of the literature, for example, Sommerstein et al. (7) also raised the idea that ACEi and/or ARB could play a role in the severe course of COVID‐19. Sommerstein later revised their position after a more careful analysis (8) but the damage had already been done as the press and social media promulgated the original idea, creating anxiety with patients and physicians. Perhaps the most notorious example of bad science driving bad policy in the COVID-19 era is the hydroxychloroquine-azithromycin study (4). Despite its egregious flaws, failing even to meet expected standards established by the scientific society who published the work, the International Society of Antimicrobial Chemotherapy, it was enthusiastically endorsed at the highest level of U.S. government as having “a real chance to be one of the biggest game changers in the history of medicine,” creating untold harm. We must reverse course. Clearly, scientific rigor must prevail. Sound science guides an evidence-based approach for health care providers to treat and advise patients rationally.

As we have discussed before (10) and opposite of the conclusions reached by Abassi et al., there is no COVID-19-related evidence supporting abandonment of RAAS inhibitors for patients who are prescribed these medications for indicated conditions. This is consistent with all of the professional societies who have examined and posted their recommendations on the question.

GRANTS

This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK093501, DK110375, DK054231, and R01DK104785; National Heart, Lung, and Blood Institute Grants HL128909 and HL146818; and Foundation LeDucq.

DISCLOSURES

D. Batlle is a Founder of “Angiotensin Therapeutics Inc.”

None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

AUTHOR CONTRIBUTIONS

P.A.W. drafted manuscript; P.A.W., D.B., J.B.B., L.M.B., A.M.S., and M.A.S. edited and revised manuscript; P.A.W., D.B., J.B.B., L.M.B., A.M.S., and M.A.S. approved final version of manuscript.